What antidepressants can be safely taken with a Monoamine Oxidase Inhibitor (MAOI)?

What Antidepressants Can Be Taken with an MAOI?

No antidepressants should be routinely combined with MAOIs due to the risk of life-threatening serotonin syndrome, with absolute contraindications including SSRIs, SNRIs, and clomipramine. 1

Absolute Contraindications

The following antidepressants are strictly contraindicated with MAOIs:

• SSRIs (all agents): Including fluoxetine, sertraline, paroxetine, escitalopram, citalopram, and fluvoxamine are contraindicated due to serotonin syndrome risk 1
• SNRIs: Venlafaxine, duloxetine, desvenlafaxine, and milnacipran are contraindicated 1
• Tricyclic antidepressants (TCAs): All TCAs are contraindicated, particularly those with marked serotonergic affinity like clomipramine 1, 2
• Other MAOIs: Combining two MAOIs is absolutely contraindicated 1

Required Washout Periods

When switching between MAOIs and other antidepressants, mandatory washout periods must be observed:

• Standard washout: Wait at least 2 weeks after stopping an MAOI before starting any SSRI, SNRI, or TCA 1
• Fluoxetine exception: Wait 5 weeks after stopping fluoxetine before starting an MAOI due to its long half-life 1
• Reverse direction: Discontinue all SSRIs, SNRIs, or TCAs at least 2 weeks before starting an MAOI 1

Exceptional Circumstances: Treatment-Resistant Depression Only

In highly selected cases of treatment-resistant depression (TRD) that have failed multiple treatment modalities, combination therapy may be considered only under expert psychiatric supervision:

MAOI + TCA Combinations (Expert Use Only)

• May be considered when both TCA monotherapy and MAOI monotherapy have failed in TRD 3, 2
• Safer approach: Add the MAOI to an established TCA, or start both simultaneously with slow titration 2
• Avoid TCAs with high serotonergic affinity (particularly clomipramine) to minimize serotonin syndrome risk 2
• Published case series showed 21% of patients improved significantly with no complications when carefully monitored 3

MAOI + Other Antidepressant Combinations (Expert Use Only)

• Bupropion may be safer than serotonergic agents when combined with MAOIs, though still requires extreme caution 3
• Mirtazapine has been used in combination therapy but carries risk and requires close monitoring 4, 3

Critical Safety Warnings

Signs of Serotonin Syndrome to Monitor

When any combination is attempted (which should only occur in specialized settings), watch for:

• Mental status changes (agitation, confusion) 1
• Autonomic instability (hyperthermia, tachycardia, labile blood pressure) 1
• Neuromuscular abnormalities (tremor, rigidity, myoclonus) 1
• "Thunderclap" headache indicating hypertensive crisis 1

Common Pitfalls to Avoid

• Failure to maintain adequate washout periods is the most common cause of preventable serotonin syndrome 1
• Assuming all antidepressants are equally risky: SSRIs and clomipramine carry the highest risk; some TCAs may be relatively safer in expert hands 2
• Not educating patients: All patients on MAOIs must inform every healthcare provider about MAOI use before receiving any new medications 1

The Bottom Line for Clinical Practice

In routine clinical practice, do not combine MAOIs with any other antidepressants. 1 If a patient on an MAOI requires a different antidepressant, discontinue the MAOI, observe the appropriate washout period, then initiate the new agent. Combination therapy should only be attempted by experienced psychiatrists in specialized settings for carefully selected patients with severe TRD who have exhausted all other options. 3, 2